For crystal-impurity systems with similar structures and molecular weights, the impurity has a strong tendency to incorporate into the crystal lattice, making it difficult to obtain high purity with a single crystallization or even multiple crystallizations. In such cases, complexation of the impurity with an additive can be used to sterically prevent impurity incorporation in the host lattice. A nanofiltration membrane can be used to preferentially reject the higher molecular weight impurity complex in solution, while allowing the lower molecular weight API to permeate through. This permeate stream can be concentrated and recycled to operate the crystallization in a continuous mode with the aim of enhancing both yield and crystal purity simultaneously. In the present work, this strategy was applied to the continuous cooling crystallization of two systems in a mixed-suspension mixed-product removal (MSMPR) crystallizer from their solutions in 50:50 (by volume) water-ethanol mixed solvent. The first system consists of benzamide with 3-nitrobenzoic acid added as an impurity, while the second one is the active pharmaceutical ingredient (API) ketoprofen containing two impurities, ibuprofen and alpha,4-dimethylphenylacetic acid. A working strategy for selecting the complexing agent and nanofiltration membrane was established. For both systems, the membrane coupled continuous mode with recycle and complexation was found to have a better performance in terms of higher crystallization yield and lower impurity incorporation in crystals compared to both the batch process as well as the continuous process without recycle.

• Massachusetts Institute of Technology (MIT) (MIT)

• API

1. API
2. Continuous crystallization
3. impurity complexation
4. membrane filtration
5. Organic solvent nanofiltration
6. Research Article